Sustained release tablet containing indapamide

ABSTRACT

The present invention relates to a sustained release tablet containing indapamide and the process of manufacturing sustained release tablet containing indapamide. The tablet contains indapamide in the amount of 1.5 to 2.5% of the total mass of the tablet, lactose monohydrate in the amount of 30 to 80% of the total mass of the tablet, copovidone in the amount of 2 to 10% of the total mass of the tablet, hypromellose in the amount of 20 to 65% of the total mass of the tablet and lubricants in the amount of 0.1 to 5% of the total mass of the tablet. The process of manufacturing the sustained release tablet consists in mixing of indapamide with lactose monohydrate and copovidone and then, the mixture is moistened by purified water and the granulation process of it is performed. Next the granulate is dried, cooled, mixed with hypromellose and lubricants and compressed in tableting machine.

BACKGROUND OF THE INVENTION

1. Field of the Invention

The present invention relates to a sustained release tablet containingindapamide and the process of manufacturing sustained release tabletcontaining indapamide, known medicinal product of diuretic activityadministered in the therapy of primary hypertension.

2. Discussion of Background Information

From a specification of the patent No: EP 519820 it is known a sustainedrelease matrix tablet of indapamide and a process of its manufacturing.Sustained release is controlled by the use ofmethylhydroxypropylcellulose and polyvidone, the percentages of whichare from 30 to 50% and from 2 to 10%, respectively, of the total mass ofthe tablet. The percentages of the cellulose and polyvidone compoundspermit the sustained release of indapamide in a manner that is linearfor a period of at least eight hours and the release of 50% of the totalquantity of indapamide within a period of from 5 to 14 hours.Additionally, the percentages of cellulose and polyvidone compoundspermit the sustained release of indapamide to give blood levels inhumans of from 20 to 80 ng/ml at most after administration of the tabletby the oral route. A process for the preparation of an indapamide matrixtablet known from the patent No. EP 519820 is based on that there areused both a moist granulation technique and a direct compressiontechnique, comprising the steps as follows. First, indapamide,polyvidone and lactose are mixed, then moistened with anaqueous-alcoholic solution to yield a moist mass which is thengranulated, dried and then graded so as to obtain a granulate whosephysical characteristics allow good filling of the moulds of a rapidcompression machine. The obtained granulate is mixed withmethylhydoxypropylcellulose and lubricated with magnesium stearate andcolloidal silica. The final step is compression of the lubricatedmixture in a rotary compression machine, so as to obtain tablets havinga hardness of approximately from 60 to 75 N.

SUMMARY OF THE INVENTION

According to the invention, the tablet for the sustained releasecontaining indapamide contains indapamide in the amount 1.5 to 2.5% ofthe total mass of the tablet, lactose monohydrate in the amount of 30 to80% of the total mass of the tablet, copovidone in the amount of 2 to10% of the total mass of the tablet, hypromellose in the amount of 20 to65% of the total mass of the tablet and lubricants in the amount of 0.1to 5% of the total mass of the tablet. The aim of the use of copovidoneis to bind all tablet components. Hypromellose modifies the release ofthe active ingredient, which is indapamide.

Magnesium stearate or/and anhydrous colloidal silica are used as thelubricants.

Hypromellose viscosity is between 1,000 to 20,000 cP.

According to the invention the process of manufacturing the sustainedrelease tablet containing indapamide consists in mixing indapamide withlactose monohydrate and copovidone. Then, the mixture is moistened bypurified water and granulated. The obtained granulate is then dried,cooled, mixed with hypromellose and lubricants and compressed intableting machine.

DETAILED DESCRIPTION OF THE INVENTION

The aim of the invention was to simplify the process of manufacturingthe sustained release tablet containing indapamide. Additionally, itallowed replacing alcohol with water with improved safety of themanufacturing process and reduced its impact on the environment.

Examples of the invention are presented below:

EXAMPLE I

25 g of indapamide and 225 g of lactose monohydrate is mixed manually,the mixture is poured into a granulate-mixer together with 487 g oflactose monohydrate and is mixed within 1 minute with the main agitatorspeed 200 rpm.

Then 487 g of lactose monohydrate and 60 g of copovidone is added andall components are mixed for 1 minute with the main agitator speed 200rpm and then with the main agitator speed 200 rpm and the side agitatorspeed 400 rpm.

To the prepared mixture 100 g of purified water is added within 1 minutewith the main agitator speed 200 rpm and the side agitator speed 400rpm. Then, the granulation process is performed within 4 minutes withthe main agitator speed 400 rpm and side agitator speed 800 rpm.

Wet granulate is rubbed through the screen of 2.5 mm mesh and dried inthe fluidal drier in the temperature 40° C. to humidity content below 1%The dried granulate is sieved through the screen 1.2 mm mesh.

In the following step mixing of the granulate with the rest ofcomponents is performed in the rotary mixer with speed 20 rpm.

Into rotary mixer 642 g of granulate with 350 g of hypromellose ispoured and mixed within 10 minutes, after which 642 g of granulate isadded and is mixed within 10 minutes. Then, 350 g of hypromellose isadded with 6 g of colloidal silica and is mixed within 15 minutes, afterwhich 10 g of magnesium stearate is added and mixed within 5 minutes.

Finally tableting process of the prepared mixture is performed.

EXAMPLE II

25 g of indapamide and 225 g of lactose monohydrate is mixed manuallyand next the mixture is poured into granulate-mixer together with 507 gof lactose monohydrate and is mixed within 1 minute with the mainagitator speed 200 rpm.

Then 507 g of lactose monohydrate and 60 g of copovidone is added andall components are mixed within 1 minute with the main agitator speed200 rpm and 1 minute with the main agitator speed 200 rpm and the sideagitator speed 400 rpm.

To the mixture obtained in such way 100 g of purified water is dosedwithin 1 minute with the main agitator speed 200 rpm and the sideagitator speed 400 rpm.

Next the granulation process is performed within 4 minutes with the mainagitator speed 400 rpm and the side agitator speed 800 rpm.

Wet granulate is rubbed through a screen 2.5 mm mesh and is dried in thefluidal drier in the temperature 40° C. to humidity content below 1%.The dried granulate is sieved through the screen 1.2 mm mesh.

In the following step the mixing granulate with the rest of componentsis performed in the rotary mixer with the speed 20 rpm. Into rotarymixer 662 g of granulate with 330 g of hypromellose is poured and mixedwithin 10 minutes. Then, 662 g of the granulate is added and mixedwithin 10 minutes, after which 330 g of hypromellose together with 6 gof colloidal silica is added and mixed within 15 minutes, and next 10 gof magnesium stearate is added and mixed within 5 minutes.

Finally tableting process of the prepared mixture is performed.

The invention may be used in the industrial process of manufacturingsustained release tablets containing indapamide.

1. Sustained release tablet comprising 1.5 to 2.5% of total mass of thetablet of indapamide, 30 to 80% of total mass of the tablet of lactosemonohydrate, 2 to 10% of total mass of the tablet of copovidone, 20 to65% of total mass of the tablet of hypromellose, and 0.1 to 5% of totalmass of the tablet of lubricant, wherein the tablet is prepared by amethod comprising mixing indapamide with lactose monohydrate andcopovidone and then moisturizing the mixture with purified water andperforming granulation after which the granulate is dried, cooled, mixedwith hypromellose and lubricant and compressed in a tableting machine.2. The tablet according to claim 1, wherein said lubricant comprises atleast one of magnesium stearate and anhydrous colloidal silica.
 3. Thetablet according to claim 1, wherein the hypromellose has a viscosityfrom 1,000 to 20,000 cP.
 4. Process of manufacturing sustained releasetablet containing indapamide, comprising mixing indapamide with lactosemonohydrate and copovidone and then moisturizing the mixture withpurified water and performing granulation after which the granulate isdried, cooled, mixed with hypromellose and lubricant and compressed in atableting machine, wherein the tablet comprises 1.5 to 2.5% of totalmass of the tablet of indapamide, 30 to 80% of total mass of the tabletof lactose monohydrate, 2 to 10% of total mass of the tablet ofcopovidone, 20 to 65% of total mass of the tablet of hypromellose, and0.1 to 5% of total mass of the tablet of lubricant.
 5. The processaccording to claim 4, wherein said lubricant comprises at least one ofmagnesium stearate and anhydrous colloidal silica.
 6. The processaccording to claim 4, wherein the hypromellose has a viscosity from1,000 to 20,000 cP.